Inactivating Mast Cell Function Promotes Steady-State and Regenerative Hematopoiesis

Deeper understanding of the cellular and molecular pathways regulating hematopoiesis is critical to maximize the therapeutic potential of hematopoietic stem cells (HSCs) in curative procedures including hematopoietic stem cell transplantation (HST). We have recently identified mast cells (MCs) as therapeutically-targetable components of the HSC niche. Here, we demonstrate that mice lacking MCs display peripheral neutrophilia, expansion of bone marrow (BM) HSC populations, resistance to repeated 5-fluorouracil (5-FU) administration, and a BM genetic signature primed for hematopoietic proliferation. MC deficiency functionally altered both the hematopoietic and the stromal compartment of the BM as hematopoietic reconstitution was accelerated in wildtype mice that received MC deficient BM and in MC deficient recipients that received wildtype BM. Finally, we demonstrate that mice treated at steady state with the MC stabilizing agent ketotifen exhibit increased BM cellularity as well as expansion of phenotypic HSC populations. This work provides novel mechanistic rationale to explore mast cells as a target to enhance human BM transplants. Additionally, the potential of repurposing FDA approved mast cell targeting therapies to promote hematopoietic regeneration may provide well-tolerated treatment strategies at a fraction of the cost and development time.